The aim of the project is to develop synthetic peptide-based gene delivery systems for the treatment of metabolic disorders as well as inherited and acquired lipid disorders in hepatocytes. The hypothesis is that cell-specific, high level expression of exogenous genes can be achieved in vivo by receptor-mediated delivery using peptide-based gene delivery systems. These systems are composed of i) a DNA plasmid encoding a therapeutic gene product with an expression cassette, ii) a cationic peptide capable of binding to DNA and forming a complex with a size (<100 nanometers) amenable to accessing hepatocytes and entering the cells via endocytosis, iii) a peptide or glycopeptide ligand that binds specifically and with high affinity to a hepatocyte surface receptor, and iv) a lytic peptide that facilitates the escape of the complex from the endosomes into the cytoplasm after receptor-mediated endocytosis. The Phase l research project will aim at identifying peptides of minimal length that will generate reproducible and colloidally stable peptide/plasmid complexes that are not immunogenic and mediate effective gene delivery to hepatocytes in vivo.